p53, one of the most important tumor suppressor proteins, plays an essential role in regulating the cell cycle and apoptosis by sensing the integrity of genome. Therefore, the level of p53 protein is critical for normal cellular homeostasis, and is known to be subtly regulated by ubiquitination and deubiquitination systems. Numerous genetic alterations of p53 have been reported in all types of tumors. In hematopoietic tumors, the mutations of p53 gene are rare compared with solid tumors, which showed more than 50% frequency for p53 mutations. According to this characteristic feature of hematological tumors, the therapeutic strategy for targeting the level of p53 may be valuable in anti-cancer treatment of hematological tumors. Herein, we deal with the post-translational regulation of p53 via its specific ubiquitinating enzymes (Mdm2, Mdmx, COP1, Pirh2, ARF-BP1/Mule, and CHIP) and a deubiquitinating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP). In this article, we review the regulatory mechanism of p53 via ubiquitination and deubiquitination system and suggest the several possible therapeutic strategies of targeting HAUSP, a deubiquitinating enzyme for p53, for treating hematopoietic tumors.